Inhibition of IL-1, IL-6, and TNF-α in immune-mediated inflammatory diseases

Blockade of cytokines, particularly of tumour necrosis factor alpha (TNF-α), in immuno-inflammatory diseases, has led to the greatest advances in medicine of recent years. We did a thorough review of the literature with a focus on inflammation models in rodents on modified gene expression or bioactivity for IL-1, IL-6, and TNF-α, and we summarized the results of randomized controlled clinical trials in human disease. What we have learned herewith is that important information can be achieved by the use of animal models in complex, immune-mediated diseases. However, a clear ranking for putative therapeutic targets appears difficult to obtain from an experimental approach alone. This is primarily due to the fact that none of the disease models has proven to cover more than one crucial pathogenetic aspect of the complex cascade of events leading to characteristic clinical disease signs and symptoms. This supports the notion that the addressed human immune-mediated diseases are polygenic and the summation of genetic, perhaps epigenetic, and environmental factors. Nevertheless, it has become apparent, so far, that TNF-α is of crucial importance in the development of antigen-dependent and antigen-independent models of inflammation, and that these results correlate well with clinical success. With some delay, clinical trials in conditions having some relationship with rheumatoid arthritis (RA) indicate new opportunities for blocking IL-1 or IL-6 therapeutically. It appears, therefore, that a translational approach with critical, mutual reflection of simultaneously performed experiments and clinical trials is important for rapid identification of new targets and development of novel treatment options in complex, immune-mediated, inflammatory disease

The remission of rheumatoid arthritis during pregnancy

Rheumatoid arthritis (RA) is an autoimmune disease that is favorably influenced by pregnancy but relapses after delivery. A variety of circulating factors has been considered as candidates for inducing gestational improvement of RA; however, the factors/pathways responsible remain still elusive. This review discusses recent research on the effect of pregnancy on RA with a focus on immunregulation, cytokine secretion, HLA antigens, microchimerism, and innate immunity. The complex hormonal and immunological alterations of pregnancy may temporarily correct the disturbed immunregulation of R

Equilibrium and Fractional Crystallization Experiments at 0·7 GPa; the Effect of Pressure on Phase Relations and Liquid Compositions of Tholeiitic Magmas

Two series of anhydrous experiments have been performed in an end-loaded piston cylinder apparatus on a primitive, mantle-derived tholeiitic basalt at 0·7 GPa pressure and temperatures in the range 1060-1270°C. The first series are equilibrium crystallization experiments on a single basaltic bulk composition; the second series are fractionation experiments where near-perfect fractional crystallization was approached in a stepwise manner using 30°C temperature increments and starting compositions corresponding to that of the previous, higher temperature glass. At 0·7 GPa liquidus temperatures are lowered and the stability of olivine and plagioclase is enhanced with respect to clinopyroxene compared with phase equilibria of the same composition at 1·0 GPa. The residual solid assemblages of fractional crystallization experiments at 0·7 GPa evolve from dunites, followed by wehrlites, gabbronorites, and gabbros, to diorites and ilmenite-bearing diorites. In equilibrium crystallization experiments at 0·7 GPa dunites are followed by plagioclase-bearing websterites and gabbronorites. In contrast to low-pressure fractionation of tholeiitic liquids (1 bar-0·5 GPa), where early plagioclase saturation leads to the production of troctolites followed by (olivine) gabbros at an early stage of differentiation, pyroxene still crystallizes before or with plagioclase at 0·7 GPa. The liquids formed by fractional crystallization at 0·7 GPa evolve through limited silica increase with rather strong iron enrichment following the typical tholeiitic differentiation path from basalts to ferro-basalts. Silica enrichment and a decrease in absolute iron and titanium concentrations are observed in the last fractionation step after ilmenite starts to crystallize, resulting in the production of an andesitic liquid. Liquids generated by equilibrium crystallization experiments at 0·7 GPa evolve through constant SiO2 increase and only limited FeO enrichment as a consequence of spinel crystallization and closed-system behaviour. Empirical calculations of the (dry) liquid densities along the liquid lines of descent at 0·7 and 1·0 GPa reveal that only differentiation at the base of the crust (1·0 GPa) results in liquids that can ascend through the crust and that will ultimately form granitoid plutonic and/or dacitic to rhyodacitic sub-volcanic to volcanic complexes; at 0·7 GPa the liquid density increases with increasing differentiation as a result of pronounced Fe enrichment, rendering it rather unlikely that such differentiated melt will reach shallow crustal level

Liquid line of descent of a basanitic liquid at 1.5Gpa: constraints on the formation of metasomatic veins

The metasomatism observed in the oceanic and continental lithosphere is generally interpreted to represent a continuous differentiation process forming anhydrous and hydrous veins plus a cryptic enrichment in the surrounding peridotite. In order to constrain the mechanisms of vein formation and potentially clarify the nature and origin of the initial metasomatic agent, we performed a series of high-pressure experiments simulating the liquid line of descent of a basanitic magma differentiating within continental or mature oceanic lithosphere. This series of experiments has been conducted in an end-loaded piston cylinder apparatus starting from an initial hydrous ne-normative basanite at 1.5GPa and temperature varying between 1,250 and 980°C. Near-pure fractional crystallization process was achieved in a stepwise manner in 30°C temperature steps and starting compositions corresponding to the liquid composition of the previous, higher-temperature glass composition. Liquids evolve progressively from basanite to peralkaline, aluminum-rich compositions without significant SiO2 variation. The resulting cumulates are characterized by an anhydrous clinopyroxene+olivine assemblage at high temperature (1,250-1,160°C), while at lower temperature (1,130-980°C), hydrous cumulates with dominantly amphibole+minor clinopyroxene, spinel, ilmenite, titanomagnetite and apatite (1,130-980°C) are formed. This new data set supports the interpretation that anhydrous and hydrous metasomatic veins could be produced during continuous differentiation processes of primary, hydrous alkaline magmas at high pressure. However, the comparison between the cumulates generated by the fractional crystallization from an initial ne-normative liquid or from hy-normative initial compositions (hawaiite or picrobasalt) indicates that for all hydrous liquids, the different phases formed upon differentiation are mostly similar even though the proportions of hydrous versus anhydrous minerals could vary significantly. This suggests that the formation of amphibole-bearing metasomatic veins observed in the lithospheric mantle could be linked to the differentiation of initial liquids ranging from ne-normative to hy-normative in composition. The present study does not resolve the question whether the metasomatism observed in lithospheric mantle is a precursor or a consequence of alkaline magmatism; however, it confirms that the percolation and differentiation of a liquid produced by a low degree of partial melting of a source similar or slightly more enriched than depleted MORB mantle could generate hydrous metasomatic veins interpreted as a potential source for alkaline magmatism by various author

The Liquid Line of Descent of Anhydrous, Mantle-Derived, Tholeiitic Liquids by Fractional and Equilibrium Crystallization—an Experimental Study at 1·0 GPa

Two series of anhydrous experiments have been performed in an end-loaded piston cylinder apparatus on a primitive, mantle-derived tholeiitic basalt at 1·0 GPa pressure and temperatures in the range 1060-1330°C. The experimental data provide constraints on phase equilibria, and solid and liquid compositions along the liquid line of descent of primary basaltic magmas differentiating in storage reservoirs located at the base of the continental crust. The first series are equilibrium crystallization experiments on a single basaltic bulk composition; the second series are fractionation experiments where near-perfect fractional crystallization was approached in a stepwise manner using 30°C temperature steps and starting compositions corresponding to the liquid composition of the previous, higher-temperature glass composition. Liquids in the fractional crystallization experiments evolve with progressive SiO2 increase from basalts to dacites, whereas the liquids in the equilibrium crystallization experiments remain basaltic and display only a moderate SiO2 increase accompanied by more pronounced Al2O3 enrichment. The principal phase equilibria controls responsible for these contrasting trends are suppression of the peritectic olivine + liquid = opx reaction and earlier plagioclase saturation in the fractionation experiments compared with the equilibrium experiments. Both crystallization processes lead to the formation of large volumes of ultramafic cumulates related to the suppression of plagioclase crystallization relative to pyroxenes at high pressures. This is in contrast to low-pressure fractionation of tholeiitic liquids, where early plagioclase saturation leads to the production of troctolites followed by (olivine-) gabbros at an early stage of differentiatio

Dissecting the Interaction of FGF8 with Receptor FGFRL1.

In mammals, the novel protein fibroblast growth factor receptor-like 1 (FGFRL1) is involved in the development of metanephric kidneys. It appears that this receptor controls a crucial transition of the induced metanephric mesenchyme to epithelial renal vesicles, which further develop into functional nephrons. FGFRL1 knockout mice lack metanephric kidneys and do not express any fibroblast growth factor (FGF) 8 in the metanephric mesenchyme, suggesting that FGFRL1 and FGF8 play a decisive role during kidney formation. FGFRL1 consists of three extracellular immunoglobulin (Ig) domains (Ig1-Ig2-Ig3), a transmembrane domain and a short intracellular domain. We have prepared the extracellular domain (Ig123), the three individual Ig domains (Ig1, Ig2, Ig3) as well as all combinations containing two Ig domains (Ig12, Ig23, Ig13) in recombinant form in human cells. All polypeptides that contain the Ig2 domain (Ig123, Ig12, Ig23, Ig2) were found to interact with FGF8 with very high affinity, whereas all constructs that lack the Ig2 domain (Ig1, Ig3, Ig13) poorly interacted with FGF8 as shown by ELISA and surface plasmon resonance. It is therefore likely that FGFRL1 represents a physiological receptor for FGF8 in the kidney and that the ligand primarily binds to the Ig2 domain of the receptor. With Biacore experiments, we also measured the affinity of FGF8 for the different constructs. All constructs containing the Ig2 domain showed a rapid association and a slow dissociation phase, from which a KD of 2-3 × 10-9 M was calculated. Our data support the hypothesis that binding of FGF8 to FGFRL1 could play an important role in driving the formation of nephrons in the developing kidney

High-resolution ultrasound confirms reduced synovial hyperplasia following rituximab treatment in rheumatoid arthritis

Objective. To assess the response of RA patients to rituximab (RTX) treatment using a sensitive imaging technique for synovitis. Methods. Twenty-three RA patients were treated with two 1000-mg infusions of the B-cell depleting antibody, RTX, in an observational protocol. Clinical response was assessed by the European League Against Rheumatism (EULAR) response criteria. High-resolution grey-scale and colour-coded power Doppler (PD) ultrasonography was performed at baseline and 6 months after RTX. The second to fifth MCP and PIP joints were bilaterally examined with joints in a neutral 0 position from a palmar view and scored from 0 to 3. Results. Median disease activity score (DAS28) improved from 5.03 to 3.56 (P = 0.001), which corresponded to a EULAR moderate response in 11 of 23 patients and a EULAR good response in another 6 patients. Improved control of disease activity by RTX was also indicated by tapering of median daily corticosteroid doses from 10 to 5 mg, without flare ups. Mean grey-scale scores correlated with the swollen joint count at baseline (r = 0.484, P = 0.022) and month 6 (r = 0.519, P = 0.011). Mean grey-scale scores improved upon RTX from a 0.90 median (range 0.13-1.87) to 0.75 (range 0.19-1.50, P = 0.023). Frequency of PD positive joints was low (6.1%) at baseline and did not significantly change following RTX treatment. Conclusions. High-resolution grey-scale ultrasonography (US) examination confirmed reduced synovial hyperplasia, but the applied PD method displayed no significant changes. Therefore, only grey-scale US is recommended in follow-up examinations after RTX treatmen

Patients with diffuse idiopathic skeletal hyperostosis do not have increased peripheral bone mineral density and geometry

Objectives. Recent studies have suggested that areal BMD (aBMD) measured by DXA is elevated in patients with DISH. We used peripheral QCT (pQCT) to assess volumetric BMD (vBMD) and bone geometry of the radius, tibia and the third metacarpal bone. Methods. Patients with established DISH and a control group of healthy individuals were recruited. pQCT measurements were performed at the distal epiphyses and mid-shafts of the radius, the tibia and the third metacarpal bone. At the epiphyses cross-sectional area (CSA), total BMD and trabecular BMD were measured. At the shafts, total bone CSA, cortical CSA, cortical wall thickness and cortical BMD were determined. In addition, muscle and fat CSA of the forearm and lower leg were assessed. Bone parameters were compared between the two groups using independent t-tests. Results. Thirty DISH patients and 30 controls comparable with regard to age and height were included in this study. None of the measured bone parameters differed between groups. Conclusions. In contrast to suggestions based on DXA, pQCT revealed that DISH patients do not have increased vBMD and bone geometry in the appendicular skeleton. Ossification at tendon or ligament insertion sites may lead to overestimation of aBMD if assessed by DX

Intravascular Polarimetry: Clinical Translation and Future Applications of Catheter-Based Polarization Sensitive Optical Frequency Domain Imaging

Optical coherence tomography (OCT) and optical frequency domain imaging (OFDI) visualize the coronary artery wall and plaque morphology in great detail. The advent of these high-resolution intracoronary imaging modalities has propelled our understanding of coronary atherosclerosis and provided enhanced guidance for percutaneous coronary intervention. Yet, the lack of contrast between distinct tissue types and plaque compositions impedes further elucidation of the complex mechanisms that contribute to acute coronary syndrome (ACS) and hinders the prospective identification of plaques susceptible to rupture. Intravascular polarimetry with polarization-sensitive OFDI measures polarization properties of the coronary arterial wall using conventional intravascular imaging catheters. The quantitative polarization metrics display notable image contrast between several relevant coronary plaque microstructures that are difficult to identify with conventional OCT and OFDI. Tissues rich in collagen and smooth muscle cells exhibit birefringence, while lipid and macrophages cause depolarization. In this review, we describe the basic principles of intravascular polarimetry, discuss the interpretation of the polarization signatures, and outline promising avenues for future research and clinical implications